ANTIBIOTIC-INDUCED LIPOPOLYSACCHARIDE (LPS) RELEASE FROM SALMONELLA-TYPHI - DELAY BETWEEN KILLING BY CEFTAZIDIME AND IMIPENEM AND RELEASE OF LPS

It has been suggested that the antibiotic-induced release of lipopolys accharide (LPS) is an important cause of the development of septic sho ck in patients treated for severe infections caused by gram-negative b acteria. beta-Lactam antibiotics change the integrity of the bacterial cell envelope by binding to penicillin-binding proteins (PBP) in the membrane and thus may affect the amount of LPS that is released and th e kinetics of that release. In this respect, ceftazidime at intermedia te concentrations binds with a high affinity to PBP 3 and PBP la and t hus can induce filament formation in addition to killing, whereas imip enem preferentially binds to PBP 2 and PBP 1b, leading to spheroplast formation and rapid cell lysis. We investigated the effects of these a ntibiotics on the killing and the release of the radioactively labelle d LPS of Salmonella typhi Ty 21A. A mathematical model was developed t o calculate the delay between bacterial killing and LPS release, desig nated the lag time. At antibiotic concentrations inducing equal killin g, the amount of LPS released was the same for both antibiotics. Only after 6 h of incubation at antibiotic concentrations above 0.5 mu g/ml , the amount of H-3-LPS released was slightly higher (similar to 1.2-f old) in incubations with ceftazidime than in those with imipenem, and the maximum releases of the total label were 33.2% +/- 0.89% and 27.1% +/- 0.45%, respectively. Despite the clear concentration-dependent ef fect on the bacterial killing and subsequent LPS release, the lag time was independent of the antibiotic concentration. For ceftazidime as w ell as imipenem the lag time amounted to approximately 60 min. In conc lusion, our findings imply that the mechanism of antibiotic-induced LP S release is independent of the PBP affinities for these p-lactam anti biotics. Furthermore, once the organism is killed by either imipenem o r ceftazidime, the rate of LPS release from S. typhi does not differ a ccording to the antibiotic with which the organism is killed, and ther e is little difference in the relative amount of LPS released.